title: Role of Nrf2 in host defense against influenza virus in cigarette smoke-exposed mice.
abstract: Influenza virus is a common respiratory tract viral infection. Although influenza can be fatal in patients with chronic pulmonary diseases such as chronic obstructive pulmonary disease, its pathogenesis is not fully understood. The Nrf2-mediated antioxidant system is essential to protect the lungs from oxidative injury and inflammation. In the present study, we investigated the role of Nrf2 in protection against influenza virus-induced pulmonary inflammation after cigarette smoke exposure with both in vitro and in vivo approaches. For in vitro analyses, peritoneal macrophages isolated from wild-type and Nrf2-deficient mice were treated with poly(I:C) and/or cigarette smoke extract. For in vivo analysis, these mice were infected with influenza A virus with or without exposure to cigarette smoke. In Nrf2-deficient macrophages, NF-κB activation and the induction of its target inflammatory genes were enhanced after costimulation with cigarette smoke extract and poly(I:C) compared with wild-type macrophages. The induction of antioxidant genes was observed for the lungs of wild-type mice but not those of Nrf2-deficient mice after cigarette smoke exposure. Cigarette smoke-exposed Nrf2-deficient mice showed higher rates of mortality than did wild-type mice after influenza virus infection, with enhanced peribronchial inflammation, lung permeability damage, and mucus hypersecretion. Lung oxidant levels and NF-κB-mediated inflammatory gene expression in the lungs were also enhanced in Nrf2-deficient mice. Our data indicate that the antioxidant pathway controlled by Nrf2 is pivotal for protection against the development of influenza virus-induced pulmonary inflammation and injury under oxidative conditions.
authors.affiliation: Department of Respiratory Medicine, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba, Ibaraki 305, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Yageta
authors.forename: Yukio
authors.initials: Y
authors.lastname: Ishii
authors.forename: Yuko
authors.initials: Y
authors.lastname: Morishima
authors.forename: Hironori
authors.initials: H
authors.lastname: Masuko
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ano
authors.forename: Tadahiro
authors.initials: T
authors.lastname: Yamadori
authors.forename: Ken
authors.initials: K
authors.lastname: Itoh
authors.forename: Kaoru
authors.initials: K
authors.lastname: Takeuchi
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Hizawa
mesh_terms: D000818:Animals; D007249:Inflammation / Q000473:pathology; D009980:Influenza A virus / Q000276:immunology* / Q000472:pathogenicity*; D008168:Lung / Q000473:pathology; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D051267:NF-E2-Related Factor 2 / Q000172:deficiency / Q000276:immunology / Q000378:metabolism*; D009976:Orthomyxoviridae Infections / Q000276:immunology* / Q000401:mortality / Q000473:pathology; D012907:Smoking / Q000009:adverse effects*; D016019:Survival Analysis
chemical_list: D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse